In this video, Ana Kiess, MD, PhD, Johns Hopkins Medicine, Baltimore, Maryland, explores how principles from external beam radiation therapy can inform adaptive dosing strategies in radiopharmaceutical therapy. 

She reviews key concepts such as therapeutic index, absorbed dose, and biologically effective dose, emphasizing differences in dose delivery, fractionation, and repair kinetics between external beam radiation and theranostics. Drawing on emerging clinical trials and modeling studies, she discusses how modifying administered activity, cycle timing, and treatment breaks may enhance tumor control while balancing toxicity and advancing personalized dosing approaches in theranostics.

Transcript:

I am Ana Kiess, I am a radiation oncologist and associate professor of radiation oncology at Johns Hopkins University, and I am giving a brief overview of a talk that I gave at the SNMMI Theranostics Conference in November 2025. The title of this talk was “Lessons learned from external beam radiation: Adaptive vs standard dosing.” 

This title was the brainchild of Tom Hope, who was one of the organizers of the theranostics meeting this year. He always has a lot of thought-provoking questions and I think something that comes up a lot in the field of theranostics now is how we optimize our dosing, and there are a lot of trials that are exploring adaptive dosing in theranostics. He wanted me to compare some of what we do in radiation oncology with external beam radiation in the context of applying that to theranostics or radiopharmaceutical therapies.

This was a new topic for me, and it was one that I found very interesting as I prepared for the talk. Part of the talk at the beginning was more educational, going into some of the background about how radiation oncologists consider dose and how to optimize the therapeutic index, which is the ratio of the dose that causes toxicity to the dose that is effective. It is one of the key concepts in oncology across different specialties—radiation, medical, nuclear medicine—and essentially the goal of most therapies is to optimize treatment in ways that increase efficacy and decrease toxicity. One of the ways that we do this in any radiation field is to optimize the ratio of the absorbed radiation dose to the tumor vs normal tissues.

In radiation oncology, most of our treatment planning is working to achieve that goal and we have a different manner of treatment planning because we prescribe a specific absorbed dose to a target volume, which may be a tumor or an area at risk for microscopic cancer and we then back-calculate using software how to program the linear accelerator to deliver the beams that will achieve that prescription dose, typically in a uniform target volume, and at the same time minimize the dose to normal tissues. This is a process of dosimetry optimization that we perform for every external beam radiation planning case. 

In radiopharmaceutical therapy, we perform dosimetry using SPECT-CT, often post-injection, and we prescribe the administered activity. We can calculate all of the absorbed doses to tumor and normal tissues using this method, but the areas that we have control over are the prescription of the administered activity, the time between cycles, the agent itself, and other variables that differ from what we control in external beam radiation.

I also introduced a comparison of the concept of biologically effective dose. Biologically effective dose is essentially an application of equations to translate the absorbed dose to either the tumor or normal tissue—or any particular tissue—applying corrections for dose per fraction and tissue radiosensitivity to determine the biologically effective dose. When calculating a biologically effective dose for radiopharmaceutical therapy, you also have to account for the fact that the dose is given at a much slower rate over the course of days to weeks, and that there is concurrent tissue repair of DNA damage. The equations are different for calculating biologically effective dose for theranostics versus external beam radiation, but this concept is particularly useful when thinking about adaptive dosing or dose optimization because these equations account for different dose per fraction and, in the case of radiopharmaceutical therapies, the dose rate and repair rate.

One of the other topics that I discussed was why we typically give external beam radiation in small daily fractions and compared that with how we give radiopharmaceutical therapy in cycles separated by several weeks, and how that affects the cellular response to treatment. When we refer to adaptive radiation in radiation oncology, we are typically talking about adapting the target volume based on tumor response. If you have a large 6 cm tumor and after 3 weeks of therapy that tumor has shrunk to 3 cm, we adapt the beams in order to adjust the absorbed dose to match the current tumor volume. There are many other ways that we adapt radiation in radiation oncology, but that is typically what we mean when we say adaptive radiation. 

Other ways that we adapt radiation include selecting a specific prescription dose based on tumor volume, giving a higher dose in gray to gross tumors compared with microscopic disease areas, or adapting based on radiosensitivity and response, such as giving a lower dose for lymphomas because they are very radiosensitive, or for patients who have had a complete response to chemotherapy or who have already had most of their tumor burden removed surgically.

We also adapt the dose based on treatment intent, whether the goal is palliative, radical palliative, definitive, meaning for cure, or adjuvant, typically post-operative. I gave examples of biologically effective dose calculations for my own patients in these 4 treatment intents, showing that when we are doing radical palliative treatments, such as CyberKnife or stereotactic radiotherapy, we typically use large doses per fraction to deliver a very high biologically effective dose to provide long-term control. We also aim for a high biologically effective dose for definitive ablative radiation therapy when the goal is cure. These are all ways that we adapt dose and treatment planning in external beam radiation, mostly to increase the tumor-to-normal tissue ratio, but also to match treatment intent. 

When we turn to theranostics, several recent trials are exploring adaptive dosing approaches. FDA-approved agents most recently have used fixed dosing, for example, 200 millicuries every 6 weeks or every 8 weeks for up to 4 to 6 cycles. Based on PET scans, SPECT-CT dosimetry, and retrospective analyses of dose-response relationships, we know that fixed dosing at fixed intervals is unlikely to optimize therapy for all patients. We use SPECT-CT in theranostics to calculate absorbed dose, and we can then calculate biologically effective dose for a given patient and regimen. Several studies have shown that the majority of tumor absorbed dose occurs in the first few cycles of most theranostics treatments. This is partly due to tumor shrinkage, and although absorbed dose to normal organs varies somewhat between cycles, it is generally more consistent than tumor absorbed dose.

Some adaptive strategies in theranostics focus on delivering more administered activity in the first few cycles or shortening the interval between cycles to increase tumor absorbed dose and biologically effective dose. One example is the biomarker-modulated PSMA theranostics trial led by Amir Iravani, Jeremy Calais, and Tom Hope where lutetium PSMA-617 is given 1 week apart for 2 cycles, followed by a 6-week break, then repeated, and finally a last cycle 6 weeks later. This approach is particularly for patients with low PSMA-expressing disease, aiming to increase tumor absorbed dose and efficacy by using a more dose-dense administration pattern.

This concept of dose density has been used in medical oncology for decades. A common regimen of dose-dense chemotherapy for breast cancer used post-operatively has been shown to be more effective than more spaced-out regimens. A study from my colleagues at Johns Hopkins, Dr Sgouros and Dr Norry, published in the Journal of Nuclear Medicine, used a mathematical model of tumor growth and biologically effective dose to explore different regimens of lutetium PSMA. All regimens had the same cumulative administered activity but varied in scheduling. The study showed greater tumor control with fewer large cycles compared with standard fractionation, consistent with clinical observations. There are cooperative group trials, including an Alliance trial and a STAMPEDE trial, exploring adaptive dosing. Our Australian colleagues have also led in this area, including adaptive dosing in the TheraP trial and the ENZA-p trial, not by changing cycle length but by adjusting administered activity per cycle and pausing or discontinuing therapy for patients with excellent response based on PSMA PET-CT. 

Another potential strategy is incorporating treatment breaks for patients with deep responses, allowing tumor regrowth before resuming treatment. Studies from Germany have shown this can be effective with acceptable toxicity, and many centers in the United States, Europe, and Australia are incorporating treatment breaks into practice.

When putting this all together, we are still at the early stages of optimizing dose and adaptive dosing strategies in theranostics. One of our greatest tools is SPECT dosimetry, which allows calculation of tumor and normal organ absorbed dose, and biologically effective dose allows comparison across regimens. Similar to external beam radiation, we can consider adapting administered activity regimens to optimize tumor-to-normal tissue dose ratios. We can also adapt based on tumor volume and treatment intent. Many studies are exploring shorter cycle lengths or higher administered activity early in treatment, which may improve tumor-to-normal tissue dose ratios but may increase hematologic toxicity.

Conversely, trials are exploring treatment breaks and allowing tumor regrowth before resuming therapy, which may reduce toxicity but could risk resistance. We have much to learn as the field progresses, and I am very excited that we are moving toward optimization and personalization of theranostics for our patients.